Only little research has been conducted on the pharmacological underpinnings of metacognition. Here, we tested the modulatory effects of a single intravenous dose (100 ng/ml) of the N-methyl-D-aspartate-glutamate-receptor antagonist ketamine, a compound known to induce altered states of consciousness, on metacognition and its neural correlates. Fifty-three young, healthy adults completed two study phases of an episodic memory task involving both encoding and retrieval in a double-blind, placebo-controlled fMRI study. Trial-by-trial confidence ratings were collected during retrieval. Effects on the subjective state of consciousness were assessed using the 5D-ASC questionnaire. Confirming that the drug elicited a psychedelic state, there were effects of ketamine on all 5D-ASC scales. Acute ketamine administration during retrieval had deleterious effects on metacognitive sensitivity (meta-d′) and led to larger metacognitive bias, with retrieval performance (d′) and reaction times remaining unaffected. However, there was no ketamine effect on metacognitive efficiency (meta-d′/d′). Measures of the BOLD signal revealed that ketamine compared to placebo elicited higher activation of posterior cortical brain areas, including superior and inferior parietal lobe, calcarine gyrus, and lingual gyrus, albeit not specific to metacognitive confidence ratings. Ketamine administered during encoding did not significantly affect performance or brain activation. Overall, our findings suggest that ketamine impacts metacognition, leading to significantly larger metacognitive bias and deterioration of metacognitive sensitivity as well as unspecific activation increases in posterior hot zone areas of the neural correlates of consciousness.
Aim
Meta‐analyses indicate positive effects of both antipsychotic and cognitive‐behavioural interventions in subjects clinically at high risk (CHR) for psychosis in terms of a delay or prevention of psychotic disorders. However, these effects have been limited regarding social functioning and the relative efficacy of both types of interventions remains unclear. Furthermore, neuroprotective substances seem to be a promising alternative agent in psychosis‐prevention as they are associated with few and weak side‐effects.
Methods
In this multi‐centre randomized controlled trial (RCT), we investigate the effects of two interventions on transition to psychosis and social functioning: (a) an integrated preventive psychological intervention (IPPI) including stress‐/symptom‐management and social‐cognitive remediation; (b) N‐acetyl‐l‐cysteine (NAC) as a pharmacological intervention with glutamatergic, neuroprotective and anti‐inflammatory capabilities.
Results
This is a double‐blind, placebo‐controlled RCT with regard to NAC and a single‐blind RCT with regard to IPPI using a 2 × 2‐factorial design to investigate the individual and combined preventive effects of both interventions. To this aim, a total of 200 CHR subjects will be randomized stratified by site to one of four conditions: (a) IPPI and NAC; (b) IPPI and Placebo; (c) NAC and psychological stress management; (d) Placebo and psychological stress management. Interventions are delivered over 26 weeks with a follow‐up period of 12 months.
Conclusion
This paper reports on the rationale and protocol of an indicated prevention trial to detect the most effective and tolerable interventions with regard to transition to psychosis as well as improvements in social functioning, and to evaluate the synergistic effects of these interventions.
Zusammenfassung
Gegenstand und Ziel: Psychotische Störungen gehören aufgrund ihres frühen Beginns und ihren langfristigen Konsequenzen zu den teuersten psychischen Erkrankungen in Europa. Prävention könnte die gesellschaftlichen Kosten und die immense Belastung für Patienten und Familien signifikant reduzieren. Neurobiologische Befunde deuten auf eine glutamaterge Dysfunktion und ein Redoxungleichgewicht in der Pathophysiologie der Schizophrenie. Wir vermuten, dass Interventionen, die auf soziale Funktionen und glutamaterge /oxidative Signalwege abzielen, die Übergangsraten signifikant reduzieren würden. Material und Methoden: Unsere Studie ist eine randomisierte, placebokontrollierte 18-monatige Studie (6-Monate Intervention; 12 Monate Nachuntersuchung) mit 200 Probanden, die ein klinisch erhöhtes Risiko für Psychosen haben. Wir werden in einem 2x2-faktoriellen Design die präventiven Effekte einer kognitiv-behavioralen und sozial-kognitiven Intervention (IPPI) mit einer pharmakologischen Intervention mit einem pro-glutamatergen, neuroprotektiven Medikament (N-Acetylcystein) vergleichen. Ergebnisse und klinische Relevanz: Die Ergebnisse dieser Studie sollen zu neuen, gut verträglichen präventiven Interventionen führen.
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